Second-line treatment failure most often due to poor adherence in low and middle-income countries

Carole Leach-Lemens

Published: 24 February 2012

Poor
adherence rather than drug resistance appears more likely to be the cause of
virological failure among patients on second-line ART in resource-poor settings,
according to a systematic review and meta-analysis published in the advance
online edition of AIDS.

The
cumulative pooled proportion of the 2035 adults comprising the 19 studies from
eight countries in sub-Saharan Africa and Asia failing virologically was 21.8%,
23.1%, 26.7% and 38.0% at six, 12, 24 and 36 months, respectively.

The
authors note caution should be taken when reviewing these estimates as there
were considerable differences between the studies as well as substantial
statistical differences.

While
most of the studies did not provide enough information to be able to
distinguish conclusively between poor adherence and drug resistance as reasons
for virological failure, in those that did poor adherence was the primary
cause.

Nonetheless
these findings highlight the limited options available after second line in
resource-poor settings, notably where drug resistance is the cause of virological
failure.

The
researchers also stress the importance of improved access to greater virological
monitoring as well as more intensive adherence counselling before resistance
mutations develop.

The
scale-up of ART in resource-poor settings has had a considerable effect on
reducing death and disease. Standardised regimens notably simple, affordable
fixed-dose combination therapies have facilitated adherence with rates
comparable to those in resource-rich settings.

However,
in resource-poor settings limited or no access to viral load or genotyping and
poor availability of second-line options mean treatment failure often goes
undiagnosed until clinical illness emerges.

For
those failing second-line the options are severely limited. The World Health
Organization (WHO) provides some guidance for treatment yet states because of
financial difficulties many countries are unable to offer third-line options,
the authors note.

So
it is important to understand the numbers and reasons for those failing second-line
treatment regimens in resource-poor settings to be able to limit this happening
and determine what the future need for choices after second-line will be.

Virological
failure, the authors note, happens for a number of reasons. These include having
baseline drug resistance before starting treatment, the development of drug
resistance during treatment, length of time on treatment and poor adherence.

They
add, what is important in terms of programme effectiveness is to be able to
distinguish between patients who have failed because of drug resistance and
those who are non-adherent and have not yet developed resistance. The former
will need to switch to a third-line regimen while the latter needs adherence
support.

With
this in mind the authors chose to undertake a systematic review looking at the
rates and reasons for second-line treatment failure in resource-poor settings.

Nineteen
studies were identified for analysis, undertaken in Botswana,
South Africa, Malawi, Uganda,
Tanzania, Cambodia, Thailand
and China
between 2007 and 2011.

A
high proportion of those on second-line therapy were failing virologically.
Most happened within the first six months after starting ART.

Of
the seven studies reporting virological failure at six months the proportions
ranged from 8.6% (95% CI: 0.36-26.01% to 37.34% (95% CI: 31.30-43.59%).

At
24 months five studies reported failure in adults and one in children.
Proportions ranged from 8.32% (95% CI: 2.93-16.12%) to 41.15% (95% CI:
31.54-51.10%) among adults and for the children 20.58% (95% CI: 10.72-32.64%).

Of
the three reporting failure at 36 months the range was 6.4% (95% CI:
3.18-10.64%) to 57.32% (95% CI: 42.07-71.88%).

While
most of the studies (13) defined virological failure as a viral load greater
than 400 copies/mL (WHO definition) only half reported two consecutive
measures. Additionally different definitions of virological failure were used.

The
authors note the limitation of insufficient information to be able to
distinguish, from a programme perspective, between failure due to drug
resistance and failure due to non-adherence.

However,
all studies that measured adherence, they add, showed poor adherence to be a
significant risk factor for failure. For example, a study in Malawi where poor
adherence was defined as ‘ever missing a dose’ after adjustment for potential
confounders those poorly adherent were five times less likely to achieve viral
suppression (AOR: 5.70 95% CI: 1.16-27.93).

The
reported overall low levels of resistance mutation, in particular to protease
inhibitors (PIs), suggests failure for most patients is due primarily to poor
levels of adherence rather than the development of resistance, the authors
note.

They
point out that these failure rates are higher than reported rates of failure to
first-line therapy in resource-poor settings and reported rates of second-line
failure in resource-rich settings. This may be explained in part because of the
cumulative toxicity associated with nucleosides used in first- and second-line
making adherence difficult.

A
further challenge to adherence is the issue of drug shortages that have been
linked to increased treatment interruption and death.

Limitations
include a small sample size; other factors may explain failure including
drug-drug interaction in particular with tuberculosis drugs; and observational
studies present potential biases.

The
authors suggest that future studies could provide a better understanding of the
role played in second-line failure by non-adherence if they follow WHO
recommendations for management of second-line virologic failure. This guidance
recommends that after the first viral load result indicating viral rebound the
patient should receive an adherence support intervention, followed by a second
viral load test.

Results
could be assessed to determine both the effectiveness of adherence
interventions and the proportion of failure due to poor adherence.

The
need for third-line treatment options in resource-poor settings remains
critical for those failing second-line where adherence is not the issue.

While
the cost-effectiveness of viral load monitoring remains in question the authors
note that “recent costings have concluded that when the benefits of guided
regimen switches are considered viral load monitoring is cost-effective and
life saving. Improving the feasibility and reducing the cost of viral load
[testing] are important policy objectives.”

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